Our research derived monoclonal antibodies which either enhance or inhibit the lytic activity of a cloned iine of human NK cells. These antibodies, derived from fusions with spleen cells of mice immunized with the NK clone, affect lysis at the level of the killer cell. Two of these antibodies detect class I MHC gene products and two others detect class II MHC gene products; they are apparently unique in that other anticlass I or class II antibodies have no such effects on NK function. This suggests that MHC gene products are involved in some central way in NK function, perhaps serving as primitive receptor structures. It further raises the specific question why these four antibodies, or the epitopes they detect, are so unique. These findings are consistent with a model that a cell surface molecule such as an MHC glycoprotein may exert its functional role in the physiology of different cells via different structural domains of that molecule. It is our plan to examine this possibility using well-characterized human NK clones and a panel of anticlass I, anticlass II, and anti-LFA-1 monoclonal antibodies that detect different determinants on these molecules and which have different effects on NK function. (CS)